生物活性

• 描述Retinoid receptors are a family of intracellular hormone receptors consisting of retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Bexarotene is a selective activator of RXRs with EC₅₀ values of 28, 25, and 20 nM for RXRa, b, and g, respectively^[5]. In BEAS-2B cells, 1 µM bexarotene remarkably promoted UBE1L immunoblot expression 10 days following the treatment compared to vehicle-treated cells. Bexarotene treatment (0.05 – 0.5 µM) also dose-dependently inhibited BEAS-2B clonal growth^[6]. In Sprague-Dawley rats with NMU-induced tumors, daily administration of bexarotene (p.o., 100 mg/kg) for 6 weeks significantly suppressed tumor growth compared to vehicle-treated group. Bexarotene at 100 mg/kg completed regressed 72.2% of the primary tumors and partially suppressed 16.7% of the tumors. Administration of bexarotene at 10 and 30 mg/kg also showed anti-tumor efficacy with 10.5% and 27.8%, respectively, of tumors completely regressing. Compared to vehicle-administered control rats, bexarotene-treated animals showed decreased tumor burden at a dose-dependent manner with the values of 376, 121, and 95 mm² at 10, 30, and 100 mg/kg, respectively. Moreover, bexarotene treatment (100 mg/kg) significantly reduced cellular proliferation index in the NMU-induced rat mammary carcinoma model^[7].
• 作用机制Bexarotene is a synthetic high-affinity ligand for RXRs that activates the dimerization of RXR and its partner to regulate gene expression^[5].

• 动物研究
  剂量	Mice: 100 mg/kg[3] (p.o.) Dog: 25 mg/kg, 100 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[4] Dogs[4] Dose 10 mg/kg (i.v.) 100 mg/kg (p.o.) 6 mg/kg (i.v.) 100 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 22.7% (p.o.) 7.55% (p.o.) Vd 6.2 L/kg (i.v.) 0.388 L/kg (i.v.) T1/2 2.16 h (i.v.) Tmax 2.67 h (p.o.) 2 h (p.o.) Cmax 22.9 μM (i.v.) 8.09 μM (p.o.) 44.75 μM (i.v.) 23.6 μM (p.o.) AUC 28.6 μM·h (i.v.) 65.9 μM·h (p.o.) 63.7 - 133 μM·h (i.v.) 58.6 - 243 μM·h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02551718	Acute Leukemia of Ambiguous Li... more >>neage Recurrent Adult Acute Lymphoblastic Leukemia Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Lymphoblastic Leukemia Recurrent Childhood Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia Refractory Adult Acute Lymphoblastic Leukemia Refractory Childhood Acute Lymphoblastic Leukemia Collapse <<	Not Applicable	Recruiting	-	United States, Washington ... more >> Fred Hutch/University of Washington Cancer Consortium Recruiting Seattle, Washington, United States, 98109 Contact: Pamela S. Becker    206-616-1589    pbecker@u.washington.edu    Principal Investigator: Pamela S. Becker Collapse <<
  NCT00958074	Cutaneous T-cell Lymphoma Stag... more >>e I Cutaneous T-cell Lymphoma Stage II Cutaneous T-cell Lymphoma Stage III Cutaneous T-cell Lymphoma Stage IV Collapse <<	Phase 2	Terminated(Terminated due to s... more >>low accrual) Collapse <<	-	United States, Washington ... more >> Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Seattle, Washington, United States, 98109 Collapse <<
  NCT00091559	Cutaneous T-cell Lymphoma ... more >> Sezary Syndrome Mycosis Fungoides Collapse <<	Phase 2	Completed	-	-

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• 参考文献

• [1] Nieto-Rementeria N, Perez-Yarza G, et al. Bexarotene activates the p53/p73 pathway in human cutaneous T-cell lymphoma. Br J Dermatol. 2009 Mar;160(3):519-26.

  [2] Zhang C, Hazarika P, et al. Induction of apoptosis by bexarotene in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action. Clin Cancer Res. 2002 May;8(5):1234-40.

  [3] Bexarotene treatment does not clear β-Amyloid in an AD mouse model and Beagle dogs

  [4] LGD1069

  [5] Boehm MF, Zhang L, Zhi L, McClurg MR, Berger E, Wagoner M, Mais DE, Suto CM, Davies JA, Heyman RA, et al. Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. J Med Chem. 1995 Aug 4;38(16):3146-55.

  [6] Feng Q, Sekula D, Guo Y, Liu X, Black CC, Galimberti F, Shah SJ, Sempere LF, Memoli V, Andersen JB, Hassel BA, Dragnev K, Dmitrovsky E. UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther. 2008 Dec;7(12):3780-8.

  [7] Bischoff ED, Gottardis MM, Moon TE, Heyman RA, Lamph WW. Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma. Cancer Res. 1998 Feb 1;58(3):479-84.

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